This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The design of AIDS vaccines is complicated by the fact that virtually every HIV/SIV-specific adaptive immune response aimed at controlling the infection will generate activated HIV/SIV-specific CD4+ T-cells that may facilitate virus transmission or disease progression. This project is aimed at testing the hypothesis that the best correlate of protection from SIV challenge is the induction of robust and persistent SIV-specific mucosal CD8+ T-cell responses in the presence of low levels of mucosal activated CD4+CCR5+ T-cells. In this first experiment of this project, we are characterizing, in the macaque model of SIV vaccination and challenge, the immunogenicity and protection from low-dose intra-rectal challenge of vector combinations that include the most promising platforms available at this time (see table). Group-A: 6 RM Mamu-A*01+ AdHu5 AdHu5 AdHu5 Group-B: 6 RM Mamu-A*01+ DNA/EP AdC6 AdC7 Group-C: 6 RM Mamu-A*01+ Vaccinia AdC6 AdC7 Group-D: 6 RM Mamu-A*01+ DNA/EP Vaccinia AdC6 Group-E: 6 RM Mamu-A*01+ DNA/EP Vaccinia AdC7 Table-1: sequence of the vectors to be used in the experiments of Aim #1. At this time all animals included in this study have been identified, quarantined, and assigned to the study. The immunization phase of this study is currently in progress, and all RMs are assessed in terms of: (i) presence of systemic and mucosal CD8+ T cell responses to SIV;and (ii) levels of systemic and mucosal activated CD4+ T cells. We expect that these studies will advance our understanding of the correlates of immune protection at the level of mucosal tissues.